Current Series: Advances in Early Treatment Approaches in Multiple Sclerosis

Fred D. Lublin, MD: Let’s go back to the diagnostic work-up. Pat outlined that we’ve had this debate before of what’s the minimal work-up. At our place, for most the minimal work-up is a history, a physical, and an MRI [magnetic resonance imaging], and everything else depends on what the patient shows us.

But when you think about the things that you want to look for, you want to look for red flags, the ones that will make you look farther along. And there’s a very good paper that gets into this idea of misdiagnosis that David Miller, MD, published in the MS [Multiple Sclerosis] Journal in 2008 on red flags. It has really nice tables on mild, moderate, severe red flags to look for in MS. Things like persistently enhancing lesions, skin lesions, pulmonary issues, bone pain, and such. Other thoughts on diagnostic work-up?

Stephen C. Krieger, MD: I think what so much of the misdiagnosis work and the literature have looked at is not necessarily missing rare diagnoses, ones that might be indicated by the red flag, but over-ascribing an MS diagnosis to, let’s say, somewhat suggestive MRI changes in the absence of a truly compelling clinical history. The McDonald Criteria being applied to patients with fatigue, or with headaches, or with nebulous nonvertiginous dizziness, can really lead people astray. And I think that’s in some ways the biggest red flag.

When the “Miller red flags” paper came out, it was harder to make an MS diagnosis. The criteria, the bar was set higher. And now that it’s easier and the MRI requirements are lucent in a sense, to make the diagnosis earlier, we really do run the risk of making it erroneously in patients who may not have a disease, not necessarily some other rare disease.

Patricia K. Coyle, MD: If you look at the patients who were misdiagnosed migraine with lesions on a brain MRI—middle-aged, in their 50s or 60s with small vessel disease, lesions on the brain, MRI—overinterpretation without the critical setting of a clinically isolated syndrome.

Amit Bar-Or, MD, FRCP: I think that’s all true. One of the challenges, of course, is the recognition that there’s this entity of RIS, or radiologically isolated syndrome. And we know that there are people who can live a full life with MS and be found to have had MS on autopsy. This is almost certainly uncommon, although we clearly don’t know the numbers and the denominator. But the challenge of understanding when someone has what looks like MS on an MRI without having had any clinical presentation, or maybe some fatigue, and whether that’s related. And so, again, this is where the laboratory diagnostic tests can come in as an added value.

Patricia K. Coyle, MD: I think it’s interesting. They presented the 10-year data on the global RIS registry, 51% had presented clinically with MS.

Fred D. Lublin, MD: Just to expand on that, of course we wouldn’t want to treat people if they were truly asymptomatic throughout their life, but I think the problem is that people can have cerebral lesions and have cognitive impairment, and it’s very hard to know what is age appropriate, cognitive performance.

Stephen C. Krieger, MD: And in that RIS 10-year follow-up, 2 of the most important drivers for who among those people are destined to have clinically demonstrable MS were positive spinal fluid, and the presence of spinal cord lesions. Two things that I think tell us something about the disease process and the riskier lesions, the ones that are more likely to drive clinical signs and disability as time passes.